Studies on macrolide antibiotics I. Synthesis and antibacterial activity of erythromycin A 9-O-substituted oxime ether derivatives against Mycobacterium avium complex

A series of erythromycin A 9-O-substituted oxime ether derivatives have been synthesized and evaluated for antibacterial activity against Mycobacterium avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strains than clarithromycin (2), although in vitro antibacterial activities of these compounds were less than that of 2 against Staphylococcus aureus. Our studies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-position were found to significantly influenced the anti-MAC activity, especially against macrolide-resistant strains. Of all the compounds prepared, erythromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phenoxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strains were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives would be promising macrolide antibiotics.     

Syntheses and Antibacterial Activities of Novel Erythromycin O-Alkylamidoximes

Introduction Macrolide antibiotics, such as erythromycin A,have been extensively used in the treatment of bacterialinfections for many years[1]. Many clinical studies haverevealed that erythromycin Aand its derivatives not on-ly have antibacterial activities but also have other bio-logical activities, such as enhanced prokinetic activi-ty[2], anti-inflammatory activity[3], and antitumor ac-tivity[4],etc..Recently, a great deal of work has been done inthis field. Many new erythromycin derivati…     

New fatty monoesters of erythromycin A

New fatty polyenic (linoleic, linolenic, arachidonic, linoelaidic) mono esters of erythromycin A have been synthesized by using various reagents such as acyl chloride, carboxylic acid anhydride, and mixed carbonic anhydride. These different ways of activating the fatty acid allowed a regioselectivity of esterification at position 2' of the desosamine ring or position 4" of the cladinose ring of erythromycin A. The in vitro antibacterial properties of these new esters against members of the resident flora of the human skin were determined and compared with those of erythromycin A. The number and the stereochemistry of the double bonds seem to play a crucial role in the expression of the in vitro antibacterial activity.     

The interaction of erythromycin with polymeric sorbents adjusted to the antibiotic molecule

Cross-linked carboxylic cationites adjusted to sorption of the antibacterial antibiotic erythromycin were obtained by radical copolymerization of methacrylic acid, erythromycin methacrylate, and ethylene glycol dimethacrylate as a cross-linking agent. Studies of the sorption and desorption of erythromycin showed that adjusted sorbents had favorable equilibrium and kinetic characteristics of sorption and the ability to reversibly desorb the antibiotic. Original Russian Text ? O.A. Pisarev, N.M. Ezhova, I.S. Garkushina, 2009, published in Zhurnal Fizicheskoi Khimii, 2009, Vol. 83, No. 1, pp. 142–146.     

Motilides, macrolides with gastrointestinal motor stimulating activity. I. O-substituted and tertiary N-substituted derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal

Chemical modifications of 8,9-anhydroerythromycin A 6,9-hemiacetal (1), which showed gastrointestinal motor stimulating (GMS) activity 10 times more potent than that of erythromycin A (EM-A), were undertaken to search for derivatives having stronger GMS activity and no antimicrobial activity; details are described in this and a subsequent paper. Displacement of a methyl group of the dimethylamino group of 1 with an ethyl group and an isopropyl group provided de(N-methyl-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal (55) and de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (58), respectively. They showed significant GMS activity and no antibacterial activity. In particular, the GMS activity of 58 was increased to 248 times that of EM-A. EM-A and the derivatives obtained in this study mimic exogenous motilin in the dog. The name "motilide", meaning a motilin-like macrolide, is proposed for this new family of macrolide compounds.     

Determination of the stereochemistry of anhydroerythromycin A, the principal degradation product of the antibiotic erythromycin A

Anhydroerythromycin A arises from the acid-catalysed degradation of erythromycin A both in vitro and in vivo. It has negligible antibacterial activity, but inhibits drug oxidation in the liver, and is responsible for unwanted drug-drug interactions. Its structure has 18 chiral centres common with erythromycin A, but C-9 (the spiro carbon) is also chiral in anhydroerythromycin and its stereochemistry has not previously been reported; both 9R- and 9S-anhydroerythromycin A are plausible structures. An understanding of the chirality at C-9 was expected to throw light on the mechanism of acid-catalysed degradation of erythromycin A, a subject that has been debated in the literature over several decades.We now report a determination of the three-dimensional structure of anhydroerythromycin A, including the stereochemistry at C-9, by NMR and molecular modelling. In parallel, the relative stereochemistry of anhydroerythromycin A 2'-acetate was determined by X-ray crystallography. Both compounds were shown to have 9R stereochemistry, and anhydroerythromycin A exhibited considerable conformational flexibility in solution.     

Precursor directed biosynthesis of an orthogonally functional erythromycin analogue: selectivity in the ribosome macrolide binding pocket

The macrolide antibiotic erythromycin A and its semisynthetic analogues have been among the most useful antibacterial agents for the treatment of infectious diseases. Using a recently developed chemical genetic strategy for precursor-directed biosynthesis and colony bioassay of 6-deoxyerythromycin D analogues, we identified a new class of alkynyl- and alkenyl-substituted macrolides with activities comparable to that of the natural product. Further analysis revealed a marked and unexpected dependence of antibiotic activity on the size and degree of unsaturation of the precursor. Based on these leads, we also report the precursor-directed biosynthesis of 15-propargyl erythromycin A, a novel antibiotic that not only is as potent as erythromycin A with respect to its ability to inhibit bacterial growth and cell-free ribosomal protein biosynthesis but also harbors an orthogonal functional group that is capable of facile chemical modification.     

Improving the Antibacterial Property of Polyethylene Terephthalate by Cold Plasma Treatment

Many studies suggest strong hydrophilicity of plasma treated polyester surfaces. However, no studies have been reported on the influence of plasma on the antibacterial activity of polyethylene terephthalate. First samples were padded with triclosan as antibacterial agent with different concentrations. Second samples were treated by oxygen plasma with different operating frequency and treating time, respectively. Afterwards, plasma treated samples were padded with triclosan in same conditions. The results revealed that the antibacterial activity slighlty increased after treating with triclosan. SEM images and FTIR spectra showed that horizontal channels were brought about on the fiber surface and then better surface roughness and wettability were obtained by plasma. Fibers were fully coated with triclosan after plasma and the antibacterial activity increased with increasing operating frequency and reaction time. Finally, the samples treated with triclosan after plasma gave acceptable results and showed the best antibacterial activity for Staphylococcus aureus and Escherichia coli.     

Phytochemical screening and in-vitro evaluation of pharmacological activities of peels of Musa sapientum and Carica papaya fruit

Aqueous, absolute and 80% ethanolic extract of fruit peels of Musa sapientum and Carica papaya were investigated for their antibacterial activity, measured by disc diffusion method and antioxidant activity, measured by four different methods. Papaya and banana peels were found to contain terpenoids, tannins, alkaloids, saponins steroid, phenols, fixed oils and fats. 80% ethanolic extract of banana peel was found to contain highest total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activity but in papaya peel, highest TPC and reducing activity was shown by water extract while, TFC and radical scavenging activity was given by 80% ethanolic extract. In banana, water extract showed highest antibacterial activity against tested bacteria while in case of papaya, absolute ethanolic extract showed highest antibacterial activity. The present study revealed that peels of banana and papaya fruits are potentially good source of antioxidant and antibacterial agents.     

Synthesis and antibacterial evaluation of new sulfanyltetrazole derivatives bearing piperidine dithiocarbamate moiety

A series of new alkyl or aryl sulfanyltetrazole derivatives containing dithiocarbamate moiety (5a–6e) were synthesized. The structures of the compounds were characterized by IR, ¹H NMR, ¹³C NMR spectra, and elemental analysis data. The present study examines the antibacterial potential of novel synthetic sulfanyltetrazole compounds against clinically important gram-positive and -negative strains. The results of screening showed that attachment of dithiocarbamate to sulfanyltetrazole derivatives results in enhancement of antibacterial activity. The compound 6d showed the best activity among the tested compounds. Also, the less polar 2,5-disubstituted sulfanyltetrazole regioisomers showed an increased antibacterial activity compared with the corresponding more polar regioisomers.     

Synthesis of novel 6,11-O-bridged bicyclic ketolides via a palladium-catalyzed bis-allylation

A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise palladium-catalyzed bis-pi-allylation. By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized. These BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good core for further modifications to study the structure-activity relationship (SAR) and to overcome bacterial resistance. [reaction: see text]     

氟化修饰显著提高碳点的抗菌活性

本文采用支化聚乙烯亚胺和乙醇制备阳离子碳点,并在其表面接枝含氟烷基链,得到一种氟化修饰的碳点材料,其对革兰氏阳性菌金黄色葡萄球菌以及革兰氏阴性菌大肠杆菌和绿脓杆菌都表现出了优异的抗菌活性,而对哺乳动物细胞具有较低的毒性。通过构效关系研究发现,氟化修饰对于碳点的抗菌活性至关重要,将含氟烷基链替换成烷烃基链会极大削弱碳点的抗菌性能。本文的结果为阳离子抗菌材料的设计提供了新的思路。     

新型抗菌肽的设计、活性研究及与磷脂相互作用的计算模拟

设计合成了多个具有2个活性序列的线性和环状多肽及具有单个活性序列的短链多肽, 研究了它们的杀菌活性, 发现其杀菌活性顺序为长链肽>环状肽>短链肽, 特别是线性的Linear-KT和Linear-KS对多种革兰氏阴性菌和阳性菌均具有较高的杀菌活性. 采用MTT法考察了Linear-KT和Linear-KS对正常细胞的毒性, 其中Linear-KS表现出较低的细胞毒性, 优于阳性对照多粘菌素B. 利用计算模拟的方法计算了多肽与细菌细胞膜中磷脂酰甘油(DMPG)的相互作用. 结果表明, 多肽和DMPG的结合能也表现出长链肽>环状肽>短链肽的规律, 特别是Linear-KT和Linear-KS具有较高的结合能. 长链肽含有2个活性序列, 可提供多个荷正电的氨基酸与荷负电的磷脂结合, 结合能较大, 杀菌活性较强. 同时, 柔性的结构及Linear-KT和Linear-KS中丝氨酸和苏氨酸的β碳上的羟基可与磷脂上的羰基形成多个氢键, 进一步增大了结合能. 计算模拟的方法为抗菌肽的杀菌活性从理论上提供了一定的依据.     

Short and efficient synthesis of a vinyl-substituted tricyclic erythromycin derivative

Tricyclic erythromycin A derivatives are known potent antibacterial agents, but the potential of substituted tricyclic erythromycin A derivatives remains largely unexplored. To study this lead, the tricyclic ring system was synthesized by an efficient three-step synthesis starting from the allylic alcohol utilizing a novel azidoisocyanate. These tricyclic analogues can be used as scaffolds to probe secondary ribosomal binding sites. [structure: see text]     

Multi-biofunctional complexes combining antiseptic copper(II) with antibiotic sulfonamide ligands: Structural, redox and antibacterial study

Copper(II) and nickel(II) complexes of sulfadimethoxine, sulfadiazine, sulfamerazine and sulfamethazine were synthesized with a good yield according to an original procedure. These complexes were first characterized by single-crystal X-ray diffraction and electrochemistry. Structural inspections showed that the antibacterial entity of ligands remains non-coordinated to metal ions in the complex high-lighting the fact that in each cluster, antiseptic activity of the metal has been associated to the antibiotic activity of the ligand. In order to confirm this possibility, antibacterial activities of the complexes were studied on several bacteria. The antibacterial activity of the complex is as important as the ligands one with the addition of antiseptic activity via the incorporation of copper ions.     

Synthesis and antibacterial activity of novel [1,2,4]triazolo [3,4-h][1,8]naphthyridine-7-carboxylic acid derivatives

Novel tricyclic fluoroquinolones,[1,2,4]triazolo[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives 4a-4h bearing carrying a functional Mannich-base moiety at the C-8 position,were synthesized and evaluated for their antimicrobial activity.The results showed that some compounds with a piperazine side chain exhibited comparable or better antibacterial activity than comparator cirprofloxacin.Furthermore,the targeted compounds also displayed a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria.In particular,compound 4h showed an MIC of 0.25 μg/mL in antibacterial assay against multiple drug-resistant Escherichia coli,which represents an about 30-fold increase of potency compared to ciprofloxacin.Thus,their excellent antibacterial activity against resistant strains suggests that triazole-fused fluoroquinolones warrant further optimization as novel anti-infective chemotherapies.     

克拉霉素的合成进展

克拉霉素属大环内酯类抗生素，是第二代红霉素产品，其抗菌谱广，抗菌活性 高，药代动力性能好，在国内外受到广泛重视，有着极其重要的应用和发展前景。 对克拉霉素研究的起源与发展、研制历程、合成过程中6－羟基甲基化选择性、活 泼基团的保护与脱保护、各种克拉霉素合成工艺路线以及最新合成方法进行了较为 详细的综述。     

Synthesis of benzimidazo-substituted 3-quinolinecarboxylic acids as antibacterial agents

The 6- and 7-(1-ethylbenzimidazolyl)-substituted 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were synthesized. Antibacterial activity was tested in vitro. Only one of the new compounds prepared showed slight antibacterial activity against one of the strains tested. So, they are of no interest as antibacterial agents.     

Silica–silver core–shell particles for antibacterial textile application

The silica–silver core–shell particles were synthesized by simple one pot chemical method and were employed on the cotton fabric as an antibacterial agent. Extremely small (1–2 nm) silver nanoparticles were attached on silica core particles of average 270 nm size. The optimum density of the nano silver particles was found which was sufficient to show good antibacterial activity as well as the suppression in their surface plasmon resonance responsible for the colour of the core–shell particle for antibacterial textile application. The change in the density and size of the particles in the shell were monitored and confirmed by direct evidence of their transmission electron micrographs and by studying surface plasmon resonance characteristics. The colony counting method of antibacterial activity testing showed excellent results and even the least silver containing core–shell particles showed 100% activity against bacterial concentration of 10⁴ colony counting units (cfu). The bonding between core–shell particles and cotton fabric was examined by X-ray photoelectron spectroscopy. The antibacterial activity test confirmed the firm attachment of core–shell particles to the cotton fabric as a result 10 times washed sample was as good antibacterial as that of unwashed sample. The bacterial growth was inhibited on and beneath the coated fabric, at the same time no zone of inhibition which occurs due to the migration of silver ions into the medium was observed indicating immobilization of silver nanoparticles on silica and core–shell particles on fabric by strong bonding.     

Sambucus Nigra Extracts–Natural Antioxidants and Antimicrobial Compounds

Due to the health-promoting properties of elderberry fruits, which result from their rich chemical composition, this raw material is widely used in herbal medicine and the food industry. The aim of the study was to demonstrate the antibacterial activity of the elderberry fruit extracts. The research showed that the content of phenolic acids and flavonoids in the extracts determined their antibacterial activity. The research showed that the content of phenolic acids and flavonoids in the extracts determined their antibacterial activity. The following phenolic acids were predominant: chlorogenic acid, sinapic acid, and t-cinnamic acid. Their average content was, respectively, 139.09, 72.84, 51.29 mg/g extract. Rutin and quercetin (their average content was 1105.39 and 306.6 mg/g extract, respectively) were the dominant flavonoids. The research showed that the elderberry polyphenol extracts exhibited activity against selected strains of bacteria within the concentration range of 0.5–0.05%. The following bacteria were the most sensitive to the extracts: Micrococcus luteus, Proteus mirabilis, Pseudomonas fragii, and Escherichia coli. Of the compounds under analysis, apigenin, kaempferol and ferulic, protocatechuic, and p-coumarin acids had the greatest influence on the high antibacterial activity of elderberry extracts. The results of the microbiological and chemical analyses of the composition of the extracts were analyzed statistically to indicate the bioactive compounds of the greatest antimicrobial significance.